Sporadic PCDH18 somatic mutations in EpCAM-positive hepatocellular carcinoma

Background The relationship between specific genome alterations and hepatocellular carcinoma (HCC) cancer stem cells (CSCs) remains unclear. In this study, we evaluated the relationship between somatic mutations and epithelial cell adhesion molecule positive ($ EpCAM^{+} $) CSCs. Methods Two patient-derived HCC samples (HCC1 and HCC2) were sorted by EpCAM expression and analyzed by whole exome sequence. We measured PCDH18 expression level in eight HCC cell lines as well as HCC1 and HCC2 by real-time quantitative RT-PCR. We validated the identified gene mutations in 57 paired of HCC and matched non-cancerous liver tissues by Sanger sequence. Results Whole exome sequencing on the sorted $ EpCAM^{+} $ and $ EpCAM^{−} $ HCC1 and HCC2 cells revealed 19,263 nonsynonymous mutations in the cording region. We selected mutations that potentially impair the function of the encoded protein. Ultimately, 60 mutations including 13 novel nonsense and frameshift mutations were identified. Among them, PCDH18 mutation was more frequently detected in sorted $ EpCAM^{+} $ cells than in $ EpCAM^{−} $ cells in HCC1 by whole exome sequences. However, we could not confirm the difference of PCDH18 mutation frequency between sorted $ EpCAM^{+} $ and $ EpCAM^{−} $ cells by Sanger sequencing, indicating that PCDH18 mutation could not explain intracellular heterogeneity. In contrast, we found novel PCDH18 mutations, including c.2556_2557delTG, c.1474C>G, c.2337A>G, and c.2976G>T, were detected in HCC1 and 3/57 (5.3%) additional HCC surgical specimens. All four HCCs with PCDH18 mutations were EpCAM-positive, suggesting that PCDH18 somatic mutations might explain the intertumor heterogeneity of HCCs in terms of the expression status of EpCAM. Furthermore, EpCAM-positive cell lines (Huh1, Huh7, HepG2, and Hep3B) had lower PCDH18 expression than EpCAM-negative cell lines (PLC/PRL/5, HLE, HLF, and SK-Hep-1), and PCDH18 knockdown in HCC2 cells slightly enhanced cell proliferation. Conclusions Our data suggest that PCDH18 is functionally suppressed in a subset of EpCAM-positive HCCs through somatic mutations, and may play a role in the development of EpCAM-positive HCCs. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Hayashi, Takehiro [verfasserIn] Yamashita, Taro Okada, Hikari Nio, Kouki Hara, Yasumasa Nomura, Yoshimoto Hayashi, Tomoyuki Asahina, Yoshiro Yoshida, Mariko Oishi, Naoki Sunagozaka, Hajime Takatori, Hajime Honda, Masao Kaneko, Shuichi

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2017

Schlagwörter:	Hepatocellular carcinoma EpCAM PCDH18 Whole exome sequencing Cancer stem cell

Anmerkung:	© The Author(s) 2017

Übergeordnetes Werk:	Enthalten in: Cancer cell international - London : BioMed Central, 2001, 17(2017), 1 vom: 23. Okt.
Übergeordnetes Werk:	volume:17 ; year:2017 ; number:1 ; day:23 ; month:10

Links:	Volltext

DOI / URN:	10.1186/s12935-017-0467-x

Katalog-ID:	SPR028588630

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520			\|a Background The relationship between specific genome alterations and hepatocellular carcinoma (HCC) cancer stem cells (CSCs) remains unclear. In this study, we evaluated the relationship between somatic mutations and epithelial cell adhesion molecule positive ($ EpCAM^{+} $) CSCs. Methods Two patient-derived HCC samples (HCC1 and HCC2) were sorted by EpCAM expression and analyzed by whole exome sequence. We measured PCDH18 expression level in eight HCC cell lines as well as HCC1 and HCC2 by real-time quantitative RT-PCR. We validated the identified gene mutations in 57 paired of HCC and matched non-cancerous liver tissues by Sanger sequence. Results Whole exome sequencing on the sorted $ EpCAM^{+} $ and $ EpCAM^{−} $ HCC1 and HCC2 cells revealed 19,263 nonsynonymous mutations in the cording region. We selected mutations that potentially impair the function of the encoded protein. Ultimately, 60 mutations including 13 novel nonsense and frameshift mutations were identified. Among them, PCDH18 mutation was more frequently detected in sorted $ EpCAM^{+} $ cells than in $ EpCAM^{−} $ cells in HCC1 by whole exome sequences. However, we could not confirm the difference of PCDH18 mutation frequency between sorted $ EpCAM^{+} $ and $ EpCAM^{−} $ cells by Sanger sequencing, indicating that PCDH18 mutation could not explain intracellular heterogeneity. In contrast, we found novel PCDH18 mutations, including c.2556_2557delTG, c.1474C>G, c.2337A>G, and c.2976G>T, were detected in HCC1 and 3/57 (5.3%) additional HCC surgical specimens. All four HCCs with PCDH18 mutations were EpCAM-positive, suggesting that PCDH18 somatic mutations might explain the intertumor heterogeneity of HCCs in terms of the expression status of EpCAM. Furthermore, EpCAM-positive cell lines (Huh1, Huh7, HepG2, and Hep3B) had lower PCDH18 expression than EpCAM-negative cell lines (PLC/PRL/5, HLE, HLF, and SK-Hep-1), and PCDH18 knockdown in HCC2 cells slightly enhanced cell proliferation. Conclusions Our data suggest that PCDH18 is functionally suppressed in a subset of EpCAM-positive HCCs through somatic mutations, and may play a role in the development of EpCAM-positive HCCs.
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author_variant	t h th t y ty h o ho k n kn y h yh y n yn t h th y a ya m y my n o no h s hs h t ht m h mh s k sk
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allfields	10.1186/s12935-017-0467-x doi (DE-627)SPR028588630 (SPR)s12935-017-0467-x-e DE-627 ger DE-627 rakwb eng Hayashi, Takehiro verfasserin aut Sporadic PCDH18 somatic mutations in EpCAM-positive hepatocellular carcinoma 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2017 Background The relationship between specific genome alterations and hepatocellular carcinoma (HCC) cancer stem cells (CSCs) remains unclear. In this study, we evaluated the relationship between somatic mutations and epithelial cell adhesion molecule positive ($ EpCAM^{+} $) CSCs. Methods Two patient-derived HCC samples (HCC1 and HCC2) were sorted by EpCAM expression and analyzed by whole exome sequence. We measured PCDH18 expression level in eight HCC cell lines as well as HCC1 and HCC2 by real-time quantitative RT-PCR. We validated the identified gene mutations in 57 paired of HCC and matched non-cancerous liver tissues by Sanger sequence. Results Whole exome sequencing on the sorted $ EpCAM^{+} $ and $ EpCAM^{−} $ HCC1 and HCC2 cells revealed 19,263 nonsynonymous mutations in the cording region. We selected mutations that potentially impair the function of the encoded protein. Ultimately, 60 mutations including 13 novel nonsense and frameshift mutations were identified. Among them, PCDH18 mutation was more frequently detected in sorted $ EpCAM^{+} $ cells than in $ EpCAM^{−} $ cells in HCC1 by whole exome sequences. However, we could not confirm the difference of PCDH18 mutation frequency between sorted $ EpCAM^{+} $ and $ EpCAM^{−} $ cells by Sanger sequencing, indicating that PCDH18 mutation could not explain intracellular heterogeneity. In contrast, we found novel PCDH18 mutations, including c.2556_2557delTG, c.1474C>G, c.2337A>G, and c.2976G>T, were detected in HCC1 and 3/57 (5.3%) additional HCC surgical specimens. All four HCCs with PCDH18 mutations were EpCAM-positive, suggesting that PCDH18 somatic mutations might explain the intertumor heterogeneity of HCCs in terms of the expression status of EpCAM. Furthermore, EpCAM-positive cell lines (Huh1, Huh7, HepG2, and Hep3B) had lower PCDH18 expression than EpCAM-negative cell lines (PLC/PRL/5, HLE, HLF, and SK-Hep-1), and PCDH18 knockdown in HCC2 cells slightly enhanced cell proliferation. Conclusions Our data suggest that PCDH18 is functionally suppressed in a subset of EpCAM-positive HCCs through somatic mutations, and may play a role in the development of EpCAM-positive HCCs. Hepatocellular carcinoma (dpeaa)DE-He213 EpCAM (dpeaa)DE-He213 PCDH18 (dpeaa)DE-He213 Whole exome sequencing (dpeaa)DE-He213 Cancer stem cell (dpeaa)DE-He213 Yamashita, Taro aut Okada, Hikari aut Nio, Kouki aut Hara, Yasumasa aut Nomura, Yoshimoto aut Hayashi, Tomoyuki aut Asahina, Yoshiro aut Yoshida, Mariko aut Oishi, Naoki aut Sunagozaka, Hajime aut Takatori, Hajime aut Honda, Masao aut Kaneko, Shuichi aut Enthalten in Cancer cell international London : BioMed Central, 2001 17(2017), 1 vom: 23. Okt. (DE-627)355989204 (DE-600)2091573-1 1475-2867 nnns volume:17 year:2017 number:1 day:23 month:10 https://dx.doi.org/10.1186/s12935-017-0467-x kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 17 2017 1 23 10
spelling	10.1186/s12935-017-0467-x doi (DE-627)SPR028588630 (SPR)s12935-017-0467-x-e DE-627 ger DE-627 rakwb eng Hayashi, Takehiro verfasserin aut Sporadic PCDH18 somatic mutations in EpCAM-positive hepatocellular carcinoma 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2017 Background The relationship between specific genome alterations and hepatocellular carcinoma (HCC) cancer stem cells (CSCs) remains unclear. In this study, we evaluated the relationship between somatic mutations and epithelial cell adhesion molecule positive ($ EpCAM^{+} $) CSCs. Methods Two patient-derived HCC samples (HCC1 and HCC2) were sorted by EpCAM expression and analyzed by whole exome sequence. We measured PCDH18 expression level in eight HCC cell lines as well as HCC1 and HCC2 by real-time quantitative RT-PCR. We validated the identified gene mutations in 57 paired of HCC and matched non-cancerous liver tissues by Sanger sequence. Results Whole exome sequencing on the sorted $ EpCAM^{+} $ and $ EpCAM^{−} $ HCC1 and HCC2 cells revealed 19,263 nonsynonymous mutations in the cording region. We selected mutations that potentially impair the function of the encoded protein. Ultimately, 60 mutations including 13 novel nonsense and frameshift mutations were identified. Among them, PCDH18 mutation was more frequently detected in sorted $ EpCAM^{+} $ cells than in $ EpCAM^{−} $ cells in HCC1 by whole exome sequences. However, we could not confirm the difference of PCDH18 mutation frequency between sorted $ EpCAM^{+} $ and $ EpCAM^{−} $ cells by Sanger sequencing, indicating that PCDH18 mutation could not explain intracellular heterogeneity. In contrast, we found novel PCDH18 mutations, including c.2556_2557delTG, c.1474C>G, c.2337A>G, and c.2976G>T, were detected in HCC1 and 3/57 (5.3%) additional HCC surgical specimens. All four HCCs with PCDH18 mutations were EpCAM-positive, suggesting that PCDH18 somatic mutations might explain the intertumor heterogeneity of HCCs in terms of the expression status of EpCAM. Furthermore, EpCAM-positive cell lines (Huh1, Huh7, HepG2, and Hep3B) had lower PCDH18 expression than EpCAM-negative cell lines (PLC/PRL/5, HLE, HLF, and SK-Hep-1), and PCDH18 knockdown in HCC2 cells slightly enhanced cell proliferation. Conclusions Our data suggest that PCDH18 is functionally suppressed in a subset of EpCAM-positive HCCs through somatic mutations, and may play a role in the development of EpCAM-positive HCCs. Hepatocellular carcinoma (dpeaa)DE-He213 EpCAM (dpeaa)DE-He213 PCDH18 (dpeaa)DE-He213 Whole exome sequencing (dpeaa)DE-He213 Cancer stem cell (dpeaa)DE-He213 Yamashita, Taro aut Okada, Hikari aut Nio, Kouki aut Hara, Yasumasa aut Nomura, Yoshimoto aut Hayashi, Tomoyuki aut Asahina, Yoshiro aut Yoshida, Mariko aut Oishi, Naoki aut Sunagozaka, Hajime aut Takatori, Hajime aut Honda, Masao aut Kaneko, Shuichi aut Enthalten in Cancer cell international London : BioMed Central, 2001 17(2017), 1 vom: 23. Okt. (DE-627)355989204 (DE-600)2091573-1 1475-2867 nnns volume:17 year:2017 number:1 day:23 month:10 https://dx.doi.org/10.1186/s12935-017-0467-x kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 17 2017 1 23 10
allfields_unstemmed	10.1186/s12935-017-0467-x doi (DE-627)SPR028588630 (SPR)s12935-017-0467-x-e DE-627 ger DE-627 rakwb eng Hayashi, Takehiro verfasserin aut Sporadic PCDH18 somatic mutations in EpCAM-positive hepatocellular carcinoma 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2017 Background The relationship between specific genome alterations and hepatocellular carcinoma (HCC) cancer stem cells (CSCs) remains unclear. In this study, we evaluated the relationship between somatic mutations and epithelial cell adhesion molecule positive ($ EpCAM^{+} $) CSCs. Methods Two patient-derived HCC samples (HCC1 and HCC2) were sorted by EpCAM expression and analyzed by whole exome sequence. We measured PCDH18 expression level in eight HCC cell lines as well as HCC1 and HCC2 by real-time quantitative RT-PCR. We validated the identified gene mutations in 57 paired of HCC and matched non-cancerous liver tissues by Sanger sequence. Results Whole exome sequencing on the sorted $ EpCAM^{+} $ and $ EpCAM^{−} $ HCC1 and HCC2 cells revealed 19,263 nonsynonymous mutations in the cording region. We selected mutations that potentially impair the function of the encoded protein. Ultimately, 60 mutations including 13 novel nonsense and frameshift mutations were identified. Among them, PCDH18 mutation was more frequently detected in sorted $ EpCAM^{+} $ cells than in $ EpCAM^{−} $ cells in HCC1 by whole exome sequences. However, we could not confirm the difference of PCDH18 mutation frequency between sorted $ EpCAM^{+} $ and $ EpCAM^{−} $ cells by Sanger sequencing, indicating that PCDH18 mutation could not explain intracellular heterogeneity. In contrast, we found novel PCDH18 mutations, including c.2556_2557delTG, c.1474C>G, c.2337A>G, and c.2976G>T, were detected in HCC1 and 3/57 (5.3%) additional HCC surgical specimens. All four HCCs with PCDH18 mutations were EpCAM-positive, suggesting that PCDH18 somatic mutations might explain the intertumor heterogeneity of HCCs in terms of the expression status of EpCAM. Furthermore, EpCAM-positive cell lines (Huh1, Huh7, HepG2, and Hep3B) had lower PCDH18 expression than EpCAM-negative cell lines (PLC/PRL/5, HLE, HLF, and SK-Hep-1), and PCDH18 knockdown in HCC2 cells slightly enhanced cell proliferation. Conclusions Our data suggest that PCDH18 is functionally suppressed in a subset of EpCAM-positive HCCs through somatic mutations, and may play a role in the development of EpCAM-positive HCCs. Hepatocellular carcinoma (dpeaa)DE-He213 EpCAM (dpeaa)DE-He213 PCDH18 (dpeaa)DE-He213 Whole exome sequencing (dpeaa)DE-He213 Cancer stem cell (dpeaa)DE-He213 Yamashita, Taro aut Okada, Hikari aut Nio, Kouki aut Hara, Yasumasa aut Nomura, Yoshimoto aut Hayashi, Tomoyuki aut Asahina, Yoshiro aut Yoshida, Mariko aut Oishi, Naoki aut Sunagozaka, Hajime aut Takatori, Hajime aut Honda, Masao aut Kaneko, Shuichi aut Enthalten in Cancer cell international London : BioMed Central, 2001 17(2017), 1 vom: 23. Okt. (DE-627)355989204 (DE-600)2091573-1 1475-2867 nnns volume:17 year:2017 number:1 day:23 month:10 https://dx.doi.org/10.1186/s12935-017-0467-x kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 17 2017 1 23 10
allfieldsGer	10.1186/s12935-017-0467-x doi (DE-627)SPR028588630 (SPR)s12935-017-0467-x-e DE-627 ger DE-627 rakwb eng Hayashi, Takehiro verfasserin aut Sporadic PCDH18 somatic mutations in EpCAM-positive hepatocellular carcinoma 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2017 Background The relationship between specific genome alterations and hepatocellular carcinoma (HCC) cancer stem cells (CSCs) remains unclear. In this study, we evaluated the relationship between somatic mutations and epithelial cell adhesion molecule positive ($ EpCAM^{+} $) CSCs. Methods Two patient-derived HCC samples (HCC1 and HCC2) were sorted by EpCAM expression and analyzed by whole exome sequence. We measured PCDH18 expression level in eight HCC cell lines as well as HCC1 and HCC2 by real-time quantitative RT-PCR. We validated the identified gene mutations in 57 paired of HCC and matched non-cancerous liver tissues by Sanger sequence. Results Whole exome sequencing on the sorted $ EpCAM^{+} $ and $ EpCAM^{−} $ HCC1 and HCC2 cells revealed 19,263 nonsynonymous mutations in the cording region. We selected mutations that potentially impair the function of the encoded protein. Ultimately, 60 mutations including 13 novel nonsense and frameshift mutations were identified. Among them, PCDH18 mutation was more frequently detected in sorted $ EpCAM^{+} $ cells than in $ EpCAM^{−} $ cells in HCC1 by whole exome sequences. However, we could not confirm the difference of PCDH18 mutation frequency between sorted $ EpCAM^{+} $ and $ EpCAM^{−} $ cells by Sanger sequencing, indicating that PCDH18 mutation could not explain intracellular heterogeneity. In contrast, we found novel PCDH18 mutations, including c.2556_2557delTG, c.1474C>G, c.2337A>G, and c.2976G>T, were detected in HCC1 and 3/57 (5.3%) additional HCC surgical specimens. All four HCCs with PCDH18 mutations were EpCAM-positive, suggesting that PCDH18 somatic mutations might explain the intertumor heterogeneity of HCCs in terms of the expression status of EpCAM. Furthermore, EpCAM-positive cell lines (Huh1, Huh7, HepG2, and Hep3B) had lower PCDH18 expression than EpCAM-negative cell lines (PLC/PRL/5, HLE, HLF, and SK-Hep-1), and PCDH18 knockdown in HCC2 cells slightly enhanced cell proliferation. Conclusions Our data suggest that PCDH18 is functionally suppressed in a subset of EpCAM-positive HCCs through somatic mutations, and may play a role in the development of EpCAM-positive HCCs. Hepatocellular carcinoma (dpeaa)DE-He213 EpCAM (dpeaa)DE-He213 PCDH18 (dpeaa)DE-He213 Whole exome sequencing (dpeaa)DE-He213 Cancer stem cell (dpeaa)DE-He213 Yamashita, Taro aut Okada, Hikari aut Nio, Kouki aut Hara, Yasumasa aut Nomura, Yoshimoto aut Hayashi, Tomoyuki aut Asahina, Yoshiro aut Yoshida, Mariko aut Oishi, Naoki aut Sunagozaka, Hajime aut Takatori, Hajime aut Honda, Masao aut Kaneko, Shuichi aut Enthalten in Cancer cell international London : BioMed Central, 2001 17(2017), 1 vom: 23. Okt. (DE-627)355989204 (DE-600)2091573-1 1475-2867 nnns volume:17 year:2017 number:1 day:23 month:10 https://dx.doi.org/10.1186/s12935-017-0467-x kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 17 2017 1 23 10
allfieldsSound	10.1186/s12935-017-0467-x doi (DE-627)SPR028588630 (SPR)s12935-017-0467-x-e DE-627 ger DE-627 rakwb eng Hayashi, Takehiro verfasserin aut Sporadic PCDH18 somatic mutations in EpCAM-positive hepatocellular carcinoma 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2017 Background The relationship between specific genome alterations and hepatocellular carcinoma (HCC) cancer stem cells (CSCs) remains unclear. In this study, we evaluated the relationship between somatic mutations and epithelial cell adhesion molecule positive ($ EpCAM^{+} $) CSCs. Methods Two patient-derived HCC samples (HCC1 and HCC2) were sorted by EpCAM expression and analyzed by whole exome sequence. We measured PCDH18 expression level in eight HCC cell lines as well as HCC1 and HCC2 by real-time quantitative RT-PCR. We validated the identified gene mutations in 57 paired of HCC and matched non-cancerous liver tissues by Sanger sequence. Results Whole exome sequencing on the sorted $ EpCAM^{+} $ and $ EpCAM^{−} $ HCC1 and HCC2 cells revealed 19,263 nonsynonymous mutations in the cording region. We selected mutations that potentially impair the function of the encoded protein. Ultimately, 60 mutations including 13 novel nonsense and frameshift mutations were identified. Among them, PCDH18 mutation was more frequently detected in sorted $ EpCAM^{+} $ cells than in $ EpCAM^{−} $ cells in HCC1 by whole exome sequences. However, we could not confirm the difference of PCDH18 mutation frequency between sorted $ EpCAM^{+} $ and $ EpCAM^{−} $ cells by Sanger sequencing, indicating that PCDH18 mutation could not explain intracellular heterogeneity. In contrast, we found novel PCDH18 mutations, including c.2556_2557delTG, c.1474C>G, c.2337A>G, and c.2976G>T, were detected in HCC1 and 3/57 (5.3%) additional HCC surgical specimens. All four HCCs with PCDH18 mutations were EpCAM-positive, suggesting that PCDH18 somatic mutations might explain the intertumor heterogeneity of HCCs in terms of the expression status of EpCAM. Furthermore, EpCAM-positive cell lines (Huh1, Huh7, HepG2, and Hep3B) had lower PCDH18 expression than EpCAM-negative cell lines (PLC/PRL/5, HLE, HLF, and SK-Hep-1), and PCDH18 knockdown in HCC2 cells slightly enhanced cell proliferation. Conclusions Our data suggest that PCDH18 is functionally suppressed in a subset of EpCAM-positive HCCs through somatic mutations, and may play a role in the development of EpCAM-positive HCCs. Hepatocellular carcinoma (dpeaa)DE-He213 EpCAM (dpeaa)DE-He213 PCDH18 (dpeaa)DE-He213 Whole exome sequencing (dpeaa)DE-He213 Cancer stem cell (dpeaa)DE-He213 Yamashita, Taro aut Okada, Hikari aut Nio, Kouki aut Hara, Yasumasa aut Nomura, Yoshimoto aut Hayashi, Tomoyuki aut Asahina, Yoshiro aut Yoshida, Mariko aut Oishi, Naoki aut Sunagozaka, Hajime aut Takatori, Hajime aut Honda, Masao aut Kaneko, Shuichi aut Enthalten in Cancer cell international London : BioMed Central, 2001 17(2017), 1 vom: 23. Okt. (DE-627)355989204 (DE-600)2091573-1 1475-2867 nnns volume:17 year:2017 number:1 day:23 month:10 https://dx.doi.org/10.1186/s12935-017-0467-x kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 17 2017 1 23 10
language	English
source	Enthalten in Cancer cell international 17(2017), 1 vom: 23. Okt. volume:17 year:2017 number:1 day:23 month:10
sourceStr	Enthalten in Cancer cell international 17(2017), 1 vom: 23. Okt. volume:17 year:2017 number:1 day:23 month:10
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Hepatocellular carcinoma EpCAM PCDH18 Whole exome sequencing Cancer stem cell
isfreeaccess_bool	true
container_title	Cancer cell international
authorswithroles_txt_mv	Hayashi, Takehiro @@aut@@ Yamashita, Taro @@aut@@ Okada, Hikari @@aut@@ Nio, Kouki @@aut@@ Hara, Yasumasa @@aut@@ Nomura, Yoshimoto @@aut@@ Hayashi, Tomoyuki @@aut@@ Asahina, Yoshiro @@aut@@ Yoshida, Mariko @@aut@@ Oishi, Naoki @@aut@@ Sunagozaka, Hajime @@aut@@ Takatori, Hajime @@aut@@ Honda, Masao @@aut@@ Kaneko, Shuichi @@aut@@
publishDateDaySort_date	2017-10-23T00:00:00Z
hierarchy_top_id	355989204
id	SPR028588630
language_de	englisch
fullrecord	<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">SPR028588630</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230519214550.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">201007s2017 xx \|\|\|\|\|o 00\| \|\|eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1186/s12935-017-0467-x</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR028588630</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)s12935-017-0467-x-e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Hayashi, Takehiro</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Sporadic PCDH18 somatic mutations in EpCAM-positive hepatocellular carcinoma</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2017</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="500" ind1=" " ind2=" "><subfield code="a">© The Author(s) 2017</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Background The relationship between specific genome alterations and hepatocellular carcinoma (HCC) cancer stem cells (CSCs) remains unclear. In this study, we evaluated the relationship between somatic mutations and epithelial cell adhesion molecule positive ($ EpCAM^{+} $) CSCs. Methods Two patient-derived HCC samples (HCC1 and HCC2) were sorted by EpCAM expression and analyzed by whole exome sequence. We measured PCDH18 expression level in eight HCC cell lines as well as HCC1 and HCC2 by real-time quantitative RT-PCR. We validated the identified gene mutations in 57 paired of HCC and matched non-cancerous liver tissues by Sanger sequence. Results Whole exome sequencing on the sorted $ EpCAM^{+} $ and $ EpCAM^{−} $ HCC1 and HCC2 cells revealed 19,263 nonsynonymous mutations in the cording region. We selected mutations that potentially impair the function of the encoded protein. Ultimately, 60 mutations including 13 novel nonsense and frameshift mutations were identified. Among them, PCDH18 mutation was more frequently detected in sorted $ EpCAM^{+} $ cells than in $ EpCAM^{−} $ cells in HCC1 by whole exome sequences. However, we could not confirm the difference of PCDH18 mutation frequency between sorted $ EpCAM^{+} $ and $ EpCAM^{−} $ cells by Sanger sequencing, indicating that PCDH18 mutation could not explain intracellular heterogeneity. In contrast, we found novel PCDH18 mutations, including c.2556_2557delTG, c.1474C>G, c.2337A>G, and c.2976G>T, were detected in HCC1 and 3/57 (5.3%) additional HCC surgical specimens. All four HCCs with PCDH18 mutations were EpCAM-positive, suggesting that PCDH18 somatic mutations might explain the intertumor heterogeneity of HCCs in terms of the expression status of EpCAM. Furthermore, EpCAM-positive cell lines (Huh1, Huh7, HepG2, and Hep3B) had lower PCDH18 expression than EpCAM-negative cell lines (PLC/PRL/5, HLE, HLF, and SK-Hep-1), and PCDH18 knockdown in HCC2 cells slightly enhanced cell proliferation. 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author	Hayashi, Takehiro
spellingShingle	Hayashi, Takehiro misc Hepatocellular carcinoma misc EpCAM misc PCDH18 misc Whole exome sequencing misc Cancer stem cell Sporadic PCDH18 somatic mutations in EpCAM-positive hepatocellular carcinoma
authorStr	Hayashi, Takehiro
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topic_title	Sporadic PCDH18 somatic mutations in EpCAM-positive hepatocellular carcinoma Hepatocellular carcinoma (dpeaa)DE-He213 EpCAM (dpeaa)DE-He213 PCDH18 (dpeaa)DE-He213 Whole exome sequencing (dpeaa)DE-He213 Cancer stem cell (dpeaa)DE-He213
topic	misc Hepatocellular carcinoma misc EpCAM misc PCDH18 misc Whole exome sequencing misc Cancer stem cell
topic_unstemmed	misc Hepatocellular carcinoma misc EpCAM misc PCDH18 misc Whole exome sequencing misc Cancer stem cell
topic_browse	misc Hepatocellular carcinoma misc EpCAM misc PCDH18 misc Whole exome sequencing misc Cancer stem cell
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title	Sporadic PCDH18 somatic mutations in EpCAM-positive hepatocellular carcinoma
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title_full	Sporadic PCDH18 somatic mutations in EpCAM-positive hepatocellular carcinoma
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journal	Cancer cell international
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author_browse	Hayashi, Takehiro Yamashita, Taro Okada, Hikari Nio, Kouki Hara, Yasumasa Nomura, Yoshimoto Hayashi, Tomoyuki Asahina, Yoshiro Yoshida, Mariko Oishi, Naoki Sunagozaka, Hajime Takatori, Hajime Honda, Masao Kaneko, Shuichi
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author-letter	Hayashi, Takehiro
doi_str_mv	10.1186/s12935-017-0467-x
title_sort	sporadic pcdh18 somatic mutations in epcam-positive hepatocellular carcinoma
title_auth	Sporadic PCDH18 somatic mutations in EpCAM-positive hepatocellular carcinoma
abstract	Background The relationship between specific genome alterations and hepatocellular carcinoma (HCC) cancer stem cells (CSCs) remains unclear. In this study, we evaluated the relationship between somatic mutations and epithelial cell adhesion molecule positive ($ EpCAM^{+} $) CSCs. Methods Two patient-derived HCC samples (HCC1 and HCC2) were sorted by EpCAM expression and analyzed by whole exome sequence. We measured PCDH18 expression level in eight HCC cell lines as well as HCC1 and HCC2 by real-time quantitative RT-PCR. We validated the identified gene mutations in 57 paired of HCC and matched non-cancerous liver tissues by Sanger sequence. Results Whole exome sequencing on the sorted $ EpCAM^{+} $ and $ EpCAM^{−} $ HCC1 and HCC2 cells revealed 19,263 nonsynonymous mutations in the cording region. We selected mutations that potentially impair the function of the encoded protein. Ultimately, 60 mutations including 13 novel nonsense and frameshift mutations were identified. Among them, PCDH18 mutation was more frequently detected in sorted $ EpCAM^{+} $ cells than in $ EpCAM^{−} $ cells in HCC1 by whole exome sequences. However, we could not confirm the difference of PCDH18 mutation frequency between sorted $ EpCAM^{+} $ and $ EpCAM^{−} $ cells by Sanger sequencing, indicating that PCDH18 mutation could not explain intracellular heterogeneity. In contrast, we found novel PCDH18 mutations, including c.2556_2557delTG, c.1474C>G, c.2337A>G, and c.2976G>T, were detected in HCC1 and 3/57 (5.3%) additional HCC surgical specimens. All four HCCs with PCDH18 mutations were EpCAM-positive, suggesting that PCDH18 somatic mutations might explain the intertumor heterogeneity of HCCs in terms of the expression status of EpCAM. Furthermore, EpCAM-positive cell lines (Huh1, Huh7, HepG2, and Hep3B) had lower PCDH18 expression than EpCAM-negative cell lines (PLC/PRL/5, HLE, HLF, and SK-Hep-1), and PCDH18 knockdown in HCC2 cells slightly enhanced cell proliferation. Conclusions Our data suggest that PCDH18 is functionally suppressed in a subset of EpCAM-positive HCCs through somatic mutations, and may play a role in the development of EpCAM-positive HCCs. © The Author(s) 2017
abstractGer	Background The relationship between specific genome alterations and hepatocellular carcinoma (HCC) cancer stem cells (CSCs) remains unclear. In this study, we evaluated the relationship between somatic mutations and epithelial cell adhesion molecule positive ($ EpCAM^{+} $) CSCs. Methods Two patient-derived HCC samples (HCC1 and HCC2) were sorted by EpCAM expression and analyzed by whole exome sequence. We measured PCDH18 expression level in eight HCC cell lines as well as HCC1 and HCC2 by real-time quantitative RT-PCR. We validated the identified gene mutations in 57 paired of HCC and matched non-cancerous liver tissues by Sanger sequence. Results Whole exome sequencing on the sorted $ EpCAM^{+} $ and $ EpCAM^{−} $ HCC1 and HCC2 cells revealed 19,263 nonsynonymous mutations in the cording region. We selected mutations that potentially impair the function of the encoded protein. Ultimately, 60 mutations including 13 novel nonsense and frameshift mutations were identified. Among them, PCDH18 mutation was more frequently detected in sorted $ EpCAM^{+} $ cells than in $ EpCAM^{−} $ cells in HCC1 by whole exome sequences. However, we could not confirm the difference of PCDH18 mutation frequency between sorted $ EpCAM^{+} $ and $ EpCAM^{−} $ cells by Sanger sequencing, indicating that PCDH18 mutation could not explain intracellular heterogeneity. In contrast, we found novel PCDH18 mutations, including c.2556_2557delTG, c.1474C>G, c.2337A>G, and c.2976G>T, were detected in HCC1 and 3/57 (5.3%) additional HCC surgical specimens. All four HCCs with PCDH18 mutations were EpCAM-positive, suggesting that PCDH18 somatic mutations might explain the intertumor heterogeneity of HCCs in terms of the expression status of EpCAM. Furthermore, EpCAM-positive cell lines (Huh1, Huh7, HepG2, and Hep3B) had lower PCDH18 expression than EpCAM-negative cell lines (PLC/PRL/5, HLE, HLF, and SK-Hep-1), and PCDH18 knockdown in HCC2 cells slightly enhanced cell proliferation. Conclusions Our data suggest that PCDH18 is functionally suppressed in a subset of EpCAM-positive HCCs through somatic mutations, and may play a role in the development of EpCAM-positive HCCs. © The Author(s) 2017
abstract_unstemmed	Background The relationship between specific genome alterations and hepatocellular carcinoma (HCC) cancer stem cells (CSCs) remains unclear. In this study, we evaluated the relationship between somatic mutations and epithelial cell adhesion molecule positive ($ EpCAM^{+} $) CSCs. Methods Two patient-derived HCC samples (HCC1 and HCC2) were sorted by EpCAM expression and analyzed by whole exome sequence. We measured PCDH18 expression level in eight HCC cell lines as well as HCC1 and HCC2 by real-time quantitative RT-PCR. We validated the identified gene mutations in 57 paired of HCC and matched non-cancerous liver tissues by Sanger sequence. Results Whole exome sequencing on the sorted $ EpCAM^{+} $ and $ EpCAM^{−} $ HCC1 and HCC2 cells revealed 19,263 nonsynonymous mutations in the cording region. We selected mutations that potentially impair the function of the encoded protein. Ultimately, 60 mutations including 13 novel nonsense and frameshift mutations were identified. Among them, PCDH18 mutation was more frequently detected in sorted $ EpCAM^{+} $ cells than in $ EpCAM^{−} $ cells in HCC1 by whole exome sequences. However, we could not confirm the difference of PCDH18 mutation frequency between sorted $ EpCAM^{+} $ and $ EpCAM^{−} $ cells by Sanger sequencing, indicating that PCDH18 mutation could not explain intracellular heterogeneity. In contrast, we found novel PCDH18 mutations, including c.2556_2557delTG, c.1474C>G, c.2337A>G, and c.2976G>T, were detected in HCC1 and 3/57 (5.3%) additional HCC surgical specimens. All four HCCs with PCDH18 mutations were EpCAM-positive, suggesting that PCDH18 somatic mutations might explain the intertumor heterogeneity of HCCs in terms of the expression status of EpCAM. Furthermore, EpCAM-positive cell lines (Huh1, Huh7, HepG2, and Hep3B) had lower PCDH18 expression than EpCAM-negative cell lines (PLC/PRL/5, HLE, HLF, and SK-Hep-1), and PCDH18 knockdown in HCC2 cells slightly enhanced cell proliferation. Conclusions Our data suggest that PCDH18 is functionally suppressed in a subset of EpCAM-positive HCCs through somatic mutations, and may play a role in the development of EpCAM-positive HCCs. © The Author(s) 2017
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title_short	Sporadic PCDH18 somatic mutations in EpCAM-positive hepatocellular carcinoma
url	https://dx.doi.org/10.1186/s12935-017-0467-x
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author2	Yamashita, Taro Okada, Hikari Nio, Kouki Hara, Yasumasa Nomura, Yoshimoto Hayashi, Tomoyuki Asahina, Yoshiro Yoshida, Mariko Oishi, Naoki Sunagozaka, Hajime Takatori, Hajime Honda, Masao Kaneko, Shuichi
author2Str	Yamashita, Taro Okada, Hikari Nio, Kouki Hara, Yasumasa Nomura, Yoshimoto Hayashi, Tomoyuki Asahina, Yoshiro Yoshida, Mariko Oishi, Naoki Sunagozaka, Hajime Takatori, Hajime Honda, Masao Kaneko, Shuichi
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up_date	2024-07-03T20:24:29.579Z
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In this study, we evaluated the relationship between somatic mutations and epithelial cell adhesion molecule positive ($ EpCAM^{+} $) CSCs. Methods Two patient-derived HCC samples (HCC1 and HCC2) were sorted by EpCAM expression and analyzed by whole exome sequence. We measured PCDH18 expression level in eight HCC cell lines as well as HCC1 and HCC2 by real-time quantitative RT-PCR. We validated the identified gene mutations in 57 paired of HCC and matched non-cancerous liver tissues by Sanger sequence. Results Whole exome sequencing on the sorted $ EpCAM^{+} $ and $ EpCAM^{−} $ HCC1 and HCC2 cells revealed 19,263 nonsynonymous mutations in the cording region. We selected mutations that potentially impair the function of the encoded protein. Ultimately, 60 mutations including 13 novel nonsense and frameshift mutations were identified. Among them, PCDH18 mutation was more frequently detected in sorted $ EpCAM^{+} $ cells than in $ EpCAM^{−} $ cells in HCC1 by whole exome sequences. However, we could not confirm the difference of PCDH18 mutation frequency between sorted $ EpCAM^{+} $ and $ EpCAM^{−} $ cells by Sanger sequencing, indicating that PCDH18 mutation could not explain intracellular heterogeneity. In contrast, we found novel PCDH18 mutations, including c.2556_2557delTG, c.1474C>G, c.2337A>G, and c.2976G>T, were detected in HCC1 and 3/57 (5.3%) additional HCC surgical specimens. All four HCCs with PCDH18 mutations were EpCAM-positive, suggesting that PCDH18 somatic mutations might explain the intertumor heterogeneity of HCCs in terms of the expression status of EpCAM. Furthermore, EpCAM-positive cell lines (Huh1, Huh7, HepG2, and Hep3B) had lower PCDH18 expression than EpCAM-negative cell lines (PLC/PRL/5, HLE, HLF, and SK-Hep-1), and PCDH18 knockdown in HCC2 cells slightly enhanced cell proliferation. 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Sporadic PCDH18 somatic mutations in EpCAM-positive hepatocellular carcinoma

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